IFNA21 - interferon alpha 21 |Elisa - Clia - Antibody - Protein

Background

Interferon Alpha 21 (IFN-α21) is one of the many subtypes of Type I interferons, a group of cytokines that play a critical role in regulating the immune response, particularly in antiviral defense and immune modulation. Type I interferons are produced in response to the detection of pathogens, primarily viruses, by pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs). These interferons are secreted by various immune and non-immune cells, particularly plasmacytoid dendritic cells (pDCs), and act on neighboring cells to establish an antiviral state and modulate immune activity.

The interferon-alpha (IFN-α) subfamily, which includes IFN-α21, is a large group of closely related proteins encoded by different genes. Despite sharing considerable structural and functional similarity, each IFN-α subtype may have unique characteristics, such as variations in antiviral potency, immune-modulatory effects, and tissue-specific activities. While IFN-α2 is the most widely studied and therapeutically used member of this subfamily, IFN-α21 shares many core functions, particularly in antiviral defense and immune regulation, though research on this specific subtype is more limited.

Protein Structure

IFN-α21, like other IFN-α subtypes, is a small cytokine typically composed of about 165-170 amino acids. It has a molecular weight of around 19-22 kDa, depending on the extent of glycosylation and other post-translational modifications.

Primary Structure:

• The IFN-α21 gene is located on chromosome 9 within the Type I interferon gene cluster, which includes other IFN-α subtypes. Its mature protein sequence begins with an N-terminal signal peptide, typically 20-24 amino acids long, which directs the protein to the secretory pathway. This signal peptide is cleaved before the protein is released from the cell, leaving the mature IFN-α21 molecule.

Secondary and Tertiary Structure:

• IFN-α21 exhibits the characteristic α-helical structure of Type I interferons, with five or six alpha-helices arranged in a tightly packed bundle. This helical structure is essential for receptor binding and functional activity.
• Cysteine residues within the protein form disulfide bonds, which help stabilize its conformation. The disulfide bonds play a critical role in maintaining the structural integrity of the cytokine, allowing it to engage its receptor complex effectively.
• The three-dimensional structure of IFN-α21 is stabilized by these alpha-helices and disulfide bonds, ensuring proper folding and receptor-binding affinity.

Quaternary Structure:

• Like other Type I interferons, IFN-α21 functions as a monomer. It binds to the heterodimeric Type I interferon receptor, composed of two subunits: IFNAR1 and IFNAR2. The binding of IFN-α21 to this receptor triggers a cascade of intracellular signaling events, leading to the activation of antiviral genes and immune regulatory mechanisms.

Post-Translational Modifications:

• Glycosylation is a common post-translational modification seen in interferons, and while specific data on the glycosylation patterns of IFN-α21 is limited, it is likely that this modification occurs, as it does in other IFN-α subtypes. Glycosylation may influence the stability, solubility, and half-life of the protein in the bloodstream.

Classification and Subtypes

IFN-α21 is part of the IFN-α subfamily within the Type I interferon family. The family consists of several cytokines, including IFN-α, IFN-β, IFN-ε, IFN-κ, and IFN-ω, all of which signal through the same receptor complex, the IFNAR (Type I interferon receptor).

Though all IFN-α subtypes interact with the same receptor and share similar biological functions, there are sequence variations between the different subtypes, which can affect their biological activity, receptor-binding affinity, and stability. These differences allow the IFN-α subtypes, including IFN-α21, to fine-tune the immune response depending on the tissue type, the nature of the infection, or other contextual factors.

Function and Biological Significance

Antiviral Activity:

The primary role of IFN-α21 is to mediate antiviral immunity. Upon secretion, IFN-α21 binds to its receptor on neighboring cells, initiating the JAK-STAT signaling pathway. This leads to the induction of several interferon-stimulated genes (ISGs), which encode proteins that directly or indirectly inhibit viral replication. These antiviral proteins include:

• Mx proteins, which inhibit viral entry into cells.
• PKR (Protein Kinase R), which blocks viral protein synthesis.
• OAS (2'-5'-Oligoadenylate Synthetase), which activates RNase L to degrade viral RNA.

By inducing the expression of these proteins, IFN-α21 helps establish an antiviral state in both infected and nearby uninfected cells, effectively limiting the spread of viral infection.

Immune Modulation:

Beyond its direct antiviral effects, IFN-α21 plays an essential role in shaping the immune response:

• It enhances the activity of natural killer (NK) cells, which are critical for early defense against virus-infected cells and tumors.
• IFN-α21 also promotes the differentiation and activation of T-helper 1 (Th1) cells, which are important for cellular immunity, especially against intracellular pathogens like viruses.
• IFN-α21 increases the expression of major histocompatibility complex (MHC) class I molecules on the surface of infected cells, improving the ability of cytotoxic T lymphocytes (CTLs) to recognize and eliminate infected or abnormal cells.

Antiproliferative and Antitumor Activity:

In addition to its antiviral and immune-modulatory effects, IFN-α21 exerts antiproliferative properties. Like other IFN-α subtypes, it can inhibit cell division and promote apoptosis (programmed cell death) in certain cancer cells. This makes IFN-α21 a potential candidate for cancer therapy, although clinical applications have largely focused on other subtypes, particularly IFN-α2.

Clinical Issues

Therapeutic Potential:

IFN-α21, like other interferon-alpha subtypes, holds significant potential for treating viral infections and cancer. However, most clinical therapies involving Type I interferons use IFN-α2, which has been extensively studied and approved for conditions such as chronic hepatitis B, hepatitis C, and certain cancers like hairy cell leukemia and melanoma.

• Viral Infections: Based on the broad antiviral activity of IFN-α subtypes, IFN-α21 may have utility in treating chronic viral infections like hepatitis B and hepatitis C. However, due to the focus on IFN-α2, there is limited clinical data on the specific use of IFN-α21 in these settings.
• Cancer Therapy: The antiproliferative and immune-activating properties of IFN-α21 suggest it could be explored for cancer therapy, particularly in enhancing immune surveillance and promoting tumor cell apoptosis. However, like viral treatments, IFN-α21 has not yet been widely used clinically for cancer.

Autoimmune and Inflammatory Diseases:

As with other Type I interferons, IFN-α21 may contribute to the pathogenesis of autoimmune diseases. For example, excessive Type I interferon production is implicated in systemic lupus erythematosus (SLE) and other autoimmune disorders. In such diseases, chronic interferon signaling can lead to inappropriate immune activation and tissue damage. The exact role of IFN-α21 in these processes is not well understood but is an area of active research.

Adverse Effects:

The use of IFN-α21 in therapy, like other interferons, may be associated with several side effects, primarily due to its potent immune-stimulatory properties. Common side effects of interferon therapy include:

• Flu-like symptoms: fever, chills, muscle aches, and fatigue.
• Gastrointestinal issues: nausea, vomiting, and diarrhea.
• Hematologic abnormalities: such as anemia, neutropenia, and thrombocytopenia.
• Neuropsychiatric effects: depression, anxiety, and cognitive disturbances can occur, especially with prolonged therapy.

The side effects of interferon therapy can sometimes limit its clinical use, and careful patient monitoring is required during treatment.

Summary

IFN-α21, a member of the Type I interferon family, plays a crucial role in antiviral defense, immune modulation, and potentially antitumor activity. It shares significant structural and functional similarities with other IFN-α subtypes, including a characteristic α-helical structure and the ability to bind the IFNAR receptor to initiate downstream signaling. While IFN-α2 is the most studied and widely used subtype in clinical settings, IFN-α21 holds promise for similar applications, particularly in viral infections and cancer therapy. Further research is needed to fully elucidate the therapeutic potential of IFN-α21 and its role in disease pathogenesis.